The studies accomplished during the first three years of this grant have established the feasibility of combination cisplatin-based intraperitoneal therapy with thiosulfate neutralization. Current results suggest that this therapy can salvage patients with small volume drug-resistant disease. Our aim is to further improve the therapeutic index of ip chemotherapy by investigating: 1) the use of selective intraperitoneal biochemical modulation; and 2) the mechanism by which sodium thiosulfate alters the metabolism of cisplatin (DDP) so as to provide selective protection of the kidneys. The ability of dipyridamole (DP) to enhance the activity of methotrexate (MTX) has been selected as a mode concentration-dependent synergistic interaction with which to test the feasibility of producing selective biochemical modulation in the peritoneal cavity where high local concentrations of dipyridamole can be attained. The specific aims of this project are: a) to determine the basic parameters of the DP/MTX interaction in human ovarian carcinoma cell lines, and test the concept of selective ip biochemical modulation in an ascitic xenograft model of human ovarian carcinoma; b) to perform a pharmacokinetic study of DP administered ip to patients with cancer involving the peritoneal cavity; and c) to undertake a phase I study of the combination of DP and MTX administered together by the ip route. In the second project, we will further investigate the use of iv thiosulfate as a neutralizing agent in combination with ip administration of DDP. We will determine how thiosulfate influences the generation of nephrotoxic species from DDP using new techniques that permit resolution and quantitation of 8 metabolites. The specific aims of this project are: a) to determine how thiosulfate affects the generation of DDP metabolites in vitro, and how it influences the pharmacokinetics of DDP metabolites in the plasma of patients receiving DDP; b) to determine whether iv thiosulfate, at doses sufficient to protect the kidneys, interferes with the antitumor activity of ip administered DDP in the Ehrlich ascites tumor model; c) to identify the metabolites which are most important with respect to toxicity to the kidneys, marrow and nerves; d) to investigate the changes that DDP produces in plasma glutathione, cyst(e)ine, and methionine in association with the generation of DDP metabolites; and e) to study the influence of thiosulfate on the generation of DDP metabolites inside human ovarian carcinoma cells.